Background: Recent studies suggest the use of non-invasive pressure support ventilation (NIPSV) in patients with acute cardiogenic pulmonary edema (ACPE). However, it remains unclear whether all patients with ACPE benefit from NIPSV. Objectives: To investigate short-term effects of NIPSV on respiratory, hemodynamic and oxygenation parameters in patients with respiratory failure due to severe ACPE and to identify factors predicting the need for intubation and in-hospital mortality. Methods: In a prospective, uncontrolled, open study, 28 patients admitted with signs and symptoms of severe respiratory distress due to ACPE were given NIPSV in addition to standardized pharmacological treatment. Physiological parameters were obtained before and after NIPSV, and intubation rate and in-hospital mortality were recorded. Results: NIPSV increased arterial oxygenation from paO2 54.2 ± 12.4 to 76.9 ± 12.6 mm Hg (p = 0.0001) and decreased respiratory frequency from 40.1 ± 8.2 to 22.4 ± 4.9 breaths/min (p = 0.0001). Significant improvements were also noted for heart rate, blood pressure and the paO2/FiO2 ratio. Four patients (14%) required intubation despite NIPSV. Patients who required intubation had lower paCO2 levels (p = 0.0002), lower serum bicarbonate concentrations (p = 0.04) and lower systolic blood pressure (p = 0.045) than patients who were successfully treated with NIPSV. Eight patients (28.5%) died during hospitalization. In patients with a paCO2 ≤35 mm Hg on admission, the in-hospital mortality was 87%, but in patients with a paCO2 >35 mm Hg the in-hospital mortality was 6%. Conclusions: NIPSV improves oxygenation and alleviates respiratory distress in patients with respiratory failure due to severe ACPE. However, a subgroup of patients with hypocapnia on admission might have a poor prognosis, with a higher risk of intubation and in-hospital mortality.